The major cause of morbidity and mortality in sickle cell disease (SCD) is tissue ischemia and infarction due to[unreadable] vascular occlusion that results in progressive organ damage. It is unclear whether the enhanced procoagulant or[unreadable] inflammatory activity observed in SCD directly contributes to the pathogenesis of sickle cell vaso-occlusive[unreadable] disease or merely reflects vascular injury caused by the sickle erythrocyte. We hypothesize that sickle erythrocytes[unreadable] initially injure the endothelium, inducing both a proinflammatory and procoagulant phenotype; we propose that the[unreadable] increased inflammation contributes to reversible vascular stasis while the coagulant pathway contributes to the[unreadable] complete stoppage of blood flow and tissue infarction. The strong interrelationships between the inflammatory and[unreadable] hemostatic pathways set up a vicious cycle that further propagates this process. Therefore, the Specific Aims for[unreadable] this project are to 1) Characterize the effects of thrombin generation and fibrin formation on the cycle of HbS-induced[unreadable] endothelial injury, inflammation and vascular stasis and 2) Define the role of the tissue factor pathway in[unreadable] the evolution of sickle cell-induced vascular pathology. We will induce SCD into mice with genetic alterations of[unreadable] specific components of the coagulation and coagulant signaling pathways using hematopoietic stem cell[unreadable] transplantation and test the effect on measures of inflammation and endothelial injury. We will also examine the[unreadable] effect of pharmacologic and genetic anticoagulant therapy in SCD mice as well as hypoxia-reoxygenation-treated[unreadable] SCD mice. We anticipate that these studies will clarify the interrelated roles of the coagulation system, vascular[unreadable] injury and inflammation in the evolution of sickle cell-induced vascular pathology. Additionally, these studies will[unreadable] provide insights into the value of targeted anticoagulant/anti-inflammatory therapies for the treatment and[unreadable] prevention of SCD vascular pathology.